The University of Pittsburgh CMCR proposes a paradigm-shifting approach to administer a series of new highly effective small molecule radiation mitigators, each with a different mechanism of action, and each delivered by novel topical biodegradable microneedle arrays. Based on the multiple successes of the past two funding cycles, the University of Pittsburgh CMCR has discovered many new small molecule radiation mitigators by targeting the oxidative lipidomics effects of ionizing irradiation. Four projects and 6 service cores will establish the time course for administration of each of 6 new drugs (as well as our established mitochondrial targeted GS-nitroxide small molecule radiation mitigator) with times of each drug release sequenced to its respective mechanism-based target in the radiation response. Project 1, Joel S. Greenberger, M.D., P.I. will utilize the mitochondria targeted anti-apoptotic drug GS-nitroxide, JP4-039, as the initial mitigator, and then using plasma and tissue signatures and pharmacokinetics (PK), administer each new radiation mitigator, by I.V. compared to topical biodegradable microneedle arrays (MNAs) that facilitate timed delivery. Project 2, Valerian Kagan, Ph.D., P.I. will discover new radiation mitigators based on cardiolipin-derived biosynthetic pathways for lipid mediators. Project 3, Hulya Bayir, M.D., P.I. will develop new small molecule radiation mitigators based on targeting necroptosis and ferroptosis. Project 4, Jian Yu, Ph.D., P.I. will discover new radiation mitigators targeted to acute compared to delayed intestinal stem cell irradiation induced damage. The Administrative Core A will oversee the programs. Core B Innovative Medicinal Chemistry, Peter Wipf, Ph.D./Detcho Stoyanovsky, Ph.D., Co-PIs, will deliver modifications of each of the new mitigators to optimize PK and sequenced delivery. Core C Radiobiological Standardization, Michael Epperly, Ph.D., P.I. will provide appropriate in vitro and mouse models representing standard and vulnerable populations. Core D Biostatistics, Hong Wang, Ph.D., P.I. will oversee calculations for efficient yet robust data generation. Core E Computational Systems Pharmacology, Ivet Bahar, Ph.D., P.I. will determine efficient sequenced times of delivery of radiation mitigators based on each mechanistic step in the total body irradiation response. Core F Lipidomics and Bioanalytical Core, Yulia Tyurina, Ph.D., P.I. will determine the optimal timing for drug delivery based on plasma and tissue signatures of oxidized phospholipid changes that follow radiation injury. Core G Imaging Radiation Pathology, Simon Watkins, Ph.D., P.I. will guide the discovery of new radiation mitigators at the level of inflammatory cell to epithelial cel interfaces during the radiation response in intestine, lung, and other organs. This CMCR will carry radiation mitigation to the next level using multiple drugs and mechanism-based timed delivery.